The overall research objective of this Program Project is to evaluate the potential beneficial or detrimental effects of dietary phytoestrogens on breast cancer progression, adipose tissue and the brain, using well-established laboratory animal models. Although phytoestrogens are consumed by older Americans for their perceived beneficial effects, these estrogenic compounds have not been adequately evaluated for safety, despite increasing consumption of these chemicals at high levels, especially among older women. The theme of this Program Project is that dosage, timing, and duration of exposure will all be determinants of the biological outcome of phytoestrogen exposure in different target tissues. Since both potential risks and benefits need to be evaluated, these studies cannot be conducted in humans for ethical reasons and can best be conducted in appropriate pre-clinical laboratory animal models. The proposed studies provide a systematic evaluation of the role that various regimens of phytoestrogen exposure may have on target organs that are of special relevance in aging, and these studies will also seek to determine the mechanism of phytoestrogen effects on these different target tissues. In summary, the overall goal of the P01 is to conduct highly interactive investigations of the effects of phytoestrogen dietary exposure using well established animal models, each having specific advantages for the study of: breast cancer progression to hormone independence, obesity and risk of diabetes, and cognitive function. This goal will be achieved through four complementary, synergistic projects: (1) Genistein and Endocrine Resistance in Breast Tumors, (2) Dietary Phytoestrogens and Adipocyte Development, (3) Dietary Estrogens and Cognitive Function During Aging, and (4) Phytoestrogen Action Through Estrogen Receptors alpha and beta. Investigators will be aided by an Administrative Core that oversees inter-project meetings and provides budgetary, reporting and external advisory needs, an Analytical and Bioavailability Core that will provide analysis and standardization of blood and tissue isoflavone levels for projects 1-3, and a Dietary, Genomics and Chemistry Synthesis Core that will provide uniform diets, gene expression profiling analysis by microarray and quantitative PCR methods, and chemical synthesis of phytoestrogens and phytoestrogen metabolites.